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To the Editor: Antidepressants can cause restless legs syndrome (RLS), which is as an adverse effect in the treatment of major depressive disorder. Here, we present the case of mirtazapine-induced RLS that improved with add-on pramipexole.

Case Report

An 80-year-old woman started showing symptoms of depression 1 year before she presented at our hospital. She had no history of depressive-episode sleep-related movement disorders, such as RLS, or periodic limb movement. Her chief complaints were anxiety, depressed mood, a severe loss of interest, and psychomotor inhibition. She scored 22 on the Hamilton Depression Rating Scale (HAM-D, 21 items). Brain MRI data, electroencephalograms, and serum hemoglobin, iron, and ferritin levels were within the normal limits for her age.

On admission, mirtazapine was initiated at 7.5 mg daily and then increased to 45 mg daily. Two days after the increase to 45 mg mirtazapine, the patient suddenly began to present restlessness of her legs, predominantly at the beginning of a night's sleep. Akathisia was ruled out because of the presence of discomfort without any subjective restlessness relieved by stretching, the nocturnal nature of the symptoms, and sleep disturbance. She was clinically diagnosed with RLS per the International Restless Legs Syndrome Study Group Rating Scale (http://irlssg.org), having a score of 25. We tried to perform polysomnography; however, she strongly refused it due to her delusion of negation.

Once pramipexole was initiated at 0.125 mg daily, RLS promptly and substantially subsided. Increasing the pramipexole dose to 0.25 mg improved the patient's depressive symptoms such as loss of interest and psychomotor inhibition. She was discharged on scoring 0 on the International Restless Legs Syndrome Study Group Rating Scale and scoring 5 on HAM-D.

Several case reports have linked RLS with mirtazapine, 5-hydroxytryptamine (5-HT)1 receptor-stimulating properties, and 5-HT2/5-HT3 receptor-blocking properties.1 In addition, mirtazapine is most likely one of the second-generation antidepressants that induce RLS.2

Discussion

Antidepressant-induced RLS has been most often observed in women and the elderly,3 which is in accordance with the characteristics of our patient. The pathophysiology of antidepressant-induced worsening of RLS remains unclear, but dopaminergic hypofunction combined with serotonergic and noradrenergic hyperfunction has been proposed as a possible cause.1 Elderly patients may be particularly vulnerable because of involved monoamine dysfunction.

Instead of antidepressants, the addition of pramipexole had a curative effect both on her depressive symptoms and the pharmacologically induced RLS. Pramipexole is a well-known treatment for RLS and a potentially efficacious augmentation strategy for antidepressants.4 In this case, pramipexole gave our patient a treatment benefit for both her depressive symptoms and RLS.

We hypothesize that patients with depression with RLS have been underestimated because of their complicated complaints or hidden sleepless symptoms. Although guidelines for pharmacological management of comorbid depression and RLS have been proposed,5 further research is essential to establish the most appropriate algorithm for treating such patients.

Dept. of Psychiatry, Jichi Medical University, Shimotsuke, Tochigi, Japan
Correspondence: Masaki Nishida, M.D., Ph.D.; e-mail:
References

1 Ağargün MY, Kara H, Ozbek H, et al.: Restless legs syndrome induced by mirtazapine. J Clin Psychiatry 2002; 63:1179Crossref, MedlineGoogle Scholar

2 Rottach KG, Schaner BM, Kirch MH, et al.: Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2008; 43:70–75Crossref, MedlineGoogle Scholar

3 Brown LK, Dedrick DL, Doggett JW, et al.: Antidepressant medication use and restless legs syndrome in patients presenting with insomnia. Sleep Med 2005; 6:443–450Crossref, MedlineGoogle Scholar

4 Cusin C, Iovieno N, Iosifescu DV, et al.: A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry 2013; 74:e636–e641Crossref, MedlineGoogle Scholar

5 Garcia-Borreguero D, Kohnen R, Silber MH, et al.: The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med 2013; 14:675–684Crossref, MedlineGoogle Scholar